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Findings suggest "less is more" and "tried and true" may benefit select patients SAN DIEGO, Dec. 10, 2023 /PRNewswire/ -- Research findings being presented at the 65th American Society of Hematology (ASH) Annual Meeting and Exposition highlight new treatment approaches that are enabling patients to live longer or better, judicious uses of older treatment approaches, and how a powerful, relatively new prognostic tool is helping identify patients who are more or less likely to benefit from both older and newer treatments. "At the ASH annual meeting, we always get excited about new treatment approaches that promise better outcomes for patients both now and in the future," said press briefing moderator Mikkael A. Sekeres, MD, of the Sylvester Comprehensive Cancer Center at the University of Miami Miller School of Medicine. "Collectively, these studies draw attention not only to new approaches that show how far we've come from the past, but also to studies telling us that 'less is more' in some cases and 'tried and true' treatment approaches can still be of great benefit to carefully selected patients," he said. In the first study, the addition of a second drug to standard therapy for previously untreated patients with myelofibrosis resulted in a clinically significant reduction in spleen size, compared with patients who received a placebo in addition to standard therapy. Two other studies presented in this session spotlight ways in which a novel prognostic tool is demonstrating its value across a range of blood cancers. Measurable residual disease, or MRD (also sometimes called minimal residual disease) refers to cancer cells that remain in the blood or bone marrow at a level that can be detected only with highly sensitive tests. Previous studies have shown that patients who are "MRD negative" (i.e., for whom high-sensitivity testing finds no evidence of remaining cancer cells in the blood or bone marrow) have better outcomes than patients who are "MRD positive" (i.e., whose blood or bone marrow still harbors extremely low levels of cancer cells). In the first of these MRD-related studies, patients with newly diagnosed chronic lymphocytic leukemia who were treated with a combination regimen of two targeted drugs saw significantly improved outcomes compared with similar patients who received standard-of-care chemotherapy. The researchers used MRD to determine how long patients in the targeted-agents group should continue treatment. In the second, researchers showed that patients with acute myeloid leukemia and FLT3+ who were MRD positive benefited from a donor stem cell transplant, while those who were MRD negative derived no additional benefit from undergoing a transplant. In the final study, researchers show that a subset of patients with lymphoma who are eligible for CAR T-cell therapy but face a wait to receive it can benefit from receiving an older treatment, namely a transplant of the patient's own stem cells. TRANSFORM-1: Addition of second targeted agent doubles spleen volume reduction in myelofibrosis 620: TRANSFORM-1: A Randomized, Double-Blind, Placebo-Controlled, Multicenter, International Phase 3 Study of Navitoclax in Combination with Ruxolitinib Versus Ruxolitinib Plus Placebo in Patients with Untreated Myelofibrosis An enlarged spleen is a key disease feature in myelofibrosis, a rare blood cancer. Among patients with myelofibrosis who had not previously been treated with a targeted drug known as a JAK inhibitor, twice as many of those who received an investigational targeted agent in addition to standard therapy had a clinically significant reduction in spleen size, compared with patients who received a placebo plus standard therapy. "Approximately twice the number of patients in the combination-treatment group, compared with the control arm, achieved the primary endpoint of spleen volume reduction of 35% or more by week 24 of treatment," said Naveen Pemmaraju, MD, professor of leukemia at the MD Anderson Cancer Center in Houston, and the study's lead author. "This is one of two global randomized, double-blind, placebo-controlled clinical trials in our field to be reported that investigate the use of two targeted agents in patients with myelofibrosis who have not yet been treated with a JAK inhibitor," he said. "These results show the feasibility and tolerability of a frontline approach with this promising two-drug combination and potentially open a new era of combination therapy to modify the course of this disease." However, symptom reduction with the two-drug combination regimen at week 24 of treatment has not yet reached statistical significance when compared with the control group, he said. "We will continue to monitor this and other key secondary endpoints over time." Myelofibrosis is caused by a genetic mutation in blood-forming stem cells in the bone marrow. These cells develop into specialized blood cells, such as red and white blood cells and platelets, that also carry the mutation. As the mutated cells multiply, they cause scar tissue to form in the bone marrow. With the bone marrow unable to produce enough normal blood cells, the spleen – a fist-sized organ located next to the stomach – tries to help out by starting to produce blood cells. This results in a buildup of blood cells that causes the spleen to enlarge, a condition known as splenomegaly. If the spleen continues to enlarge in myelofibrosis, it can be harmful to patients and it may cause early fullness feeling (early satiety), further lowering of blood cell counts, more infections, and increased bleeding or other hematologic complications. Patients with myelofibrosis can present with varied symptoms that often develop slowly but can in some cases develop quickly. Symptoms may include fatigue or weakness (caused by anemia, a shortage of red blood cells) and pain in the abdomen or back due to an enlarged spleen. Some patients with myelofibrosis can go on to develop acute myeloid leukemia, a rapidly progressing blood cancer. Myelofibrosis is most often diagnosed in people over age 50 and occurs roughly equally in men and women. In about half of patients, myelofibrosis is caused by a mutation in a gene known as JAK2V167F. In 2011, ruxolitinib, a JAK inhibitor, became the first targeted agent approved by the U.S. Food and Drug Administration to treat myelofibrosis and related conditions. Ruxolitinib reduces spleen enlargement and other symptoms, Dr. Pemmaraju said, but isn't a cure for the disease, and treatment with ruxolitinib alone doesn't work for all patients. In 2022, Dr. Pemmaraju and his colleagues published the results of a phase II non-randomized study in which they added the investigational drug navitoclax to ruxolitinib therapy in patients with myelofibrosis whose response was suboptimal or whose cancer was progressing with ruxolitinib alone. Navitoclax belongs to a family of targeted drugs known as BCLxL inhibitors that work by blocking a protein that helps keep cancer cells alive. The two-drug combination produced benefits in many of the patients, including reduced bone marrow scarring, and decreased spleen size. Following up on these results, the investigators launched the current study, TRANSFORM-1, a randomized controlled phase III trial that enrolled 252 patients (median age 69, 57% male) around the world with intermediate- or high-risk myelofibrosis who had not been previously treated with a JAK inhibitor. Patients were randomly assigned to treatment with either navitoclax plus ruxolitinib (NAV+RUX) or a placebo plus ruxolitinib (PBO+RUX). The study was double blinded, meaning that while patients were receiving treatment neither they nor their doctors knew which patients were in which treatment group. The study's primary endpoint was a reduction in spleen enlargement of at least 35%, confirmed by radiological imaging, by 24 weeks of treatment. This endpoint was chosen because it roughly correlates with an approximate 50% reduction in spleen size on a physical exam, which is considered a clinically significant reduction, Dr. Pemmaraju said. Secondary endpoints included the change in total symptom score at week 24. After a median follow up of 14.9 months, 79 patients (63.2%) in the NAV+RUX group had achieved a statistically significant reduction of at least a 35% in spleen enlargement at week 24, compared with 40 patients (31.5%) in the PBO+RUX group. At week 24, the average change in the total symptom score was –9.7 for patients treated with NAV+RUX, compared with –11.1 for those treated with PBO+RUX, a difference that was found to not be statistically significant. The most common adverse events included low blood cell counts and diarrhea. A total of 83 patients (33%) discontinued the study treatment, with the most common reason for discontinuation being adverse events. A total of 13 patients (10%) died 30 or fewer days after receiving their final dose of the study medication; six of those who died had received NAV+RUX and five PBO+RUX. Monitoring of the trial will continue as the patient dataset matures over time, Dr. Pemmaraju said, to collect additional data on symptom scores and other secondary endpoints, including the duration of spleen volume reduction, the effect of treatment on bone marrow scarring, and patients' overall survival. The study was funded by AbbVie, Inc., which manufactures navitoclax. Naveen Pemmaraju, MD, of MD Anderson Cancer Center, will present this study during an oral presentation on Sunday, December 10, 2023, at 4:45 p.m. Pacific time in Ballroom 20CD in the San Diego Convention Center. Ibrutinib plus venetoclax with duration of treatment determined by measurable residual disease outperforms standard therapy for newly diagnosed CLL 631: Ibrutinib Plus Venetoclax with MRD-Directed Duration of Treatment Is Superior to FCR and Is a New Standard of Care for Previously Untreated CLL: Report of the Phase III UK NCRI FLAIR Study Among patients with newly diagnosed chronic lymphocytic leukemia (CLL) who were treated with two targeted agents and whose duration of treatment was determined by high-sensitivity testing for residual cancer cells in the blood, 97.2% were free of cancer progression and 2% had died at three years. By comparison, progression-free survival (PFS) for patients receiving the standard of care was 76.8% with a death rate of 7%. "These results appear better than those seen in any previous phase III trial in CLL," said Professor Peter Hillmen, MB ChB, PhD, of the University of Leeds in the United Kingdom and principal investigator for the study. "They show that targeted therapy, with high-sensitivity testing used to individualize the duration of treatment, is a more effective approach than current standard therapy and represents a new gold standard for previously untreated CLL." CLL is the most common blood cancer in adults. In the United States about 19,000 new cases of CLL are diagnosed every year. The median age at diagnosis is 70. Roughly half of patients with CLL have mutated immunoglobulin genes, also known as IGHV. Patients with mutated IGHV generally have a better outlook and longer survival compared with those who have unmutated IGHV. Immunoglobulins (or antibodies) are proteins made by some lymphocytes that help protect the body against infection. The FLAIR study is a large, ongoing randomized trial in the UK that is comparing novel treatments for newly diagnosed CLL against what has been considered a standard of care, a regimen consisting of the drugs fludarabine, cyclophosphamide, and rituximab (FCR). In the current study, 523 patients with untreated CLL (71.3% male, median age 62) were randomly assigned to receive FCR or two newer agents, ibrutinib and venetoclax (I+V). These drugs are types of targeted therapy – that is, drugs targeted to specific molecules or molecular pathways in cancer cells that the cells need to survive and spread. Ibrutinib blocks cell signals that encourage leukemia cells to multiply, while venetoclax blocks a protein that helps cancer cells survive, explained Dr. Hillmen. A novel feature of the FLAIR trial is its use of measurable residual disease, or MRD, to determine how long patients should continue treatment. Previous studies in leukemia and other cancers have shown that patients who are "MRD negative" (those for whom high-sensitivity testing has found no evidence of remaining leukemia cells in the blood or bone marrow) have better outcomes than patients who are "MRD positive" (when the blood or bone marrow still harbors extremely low levels of leukemia cells that can be detected with high-sensitivity testing). In FLAIR, patients in the I+V group underwent blood tests for MRD at one year and then every six months. If these tests found no evidence of remaining leukemia cells, the testing was repeated in both the blood and the bone marrow after another three months and again three months later. If all these tests were MRD negative, the patient was treated for twice the duration of time from the start of I+V treatment to the first MRD-negative test. "Patients' duration of treatment was determined by how quickly they responded," said Prof. Hillmen. Duration of treatment ranged from two to six years. The trial's primary endpoint was PFS, while overall survival was one of several secondary endpoints. At a median follow-up of 43.7 months, patients treated with FCR were approximately eight times as likely to have disease progression compared with patients who received I+V. This finding was consistent regardless of patient gender, age, or disease stage. Moreover, patients with a worse prognosis appeared to do particularly well. "We found that the patients with disease features associated with a worse prognosis – such as those with unmutated IGHV or deletion of chromosome 11q – had even better outcomes when treated with I+V than the favorable-risk, IGHV-mutated patients," said Dr. Hillmen. "At three years follow up, patients with unmutated IGHV were about 14 times less likely to have progressed if treated with I+V than with FCR. At the latest follow-up, not a single patient with the 11q chromosome deletion who was treated with I+V had progressed or died, compared with 31.2% of patients with this deletion who were treated with FCR. This indicates that the combination of I+V overcomes previously reported risk factors for a poor outcome in patients with CLL." A limitation of the study, Prof. Hillmen said, is that patients were eligible to enroll only if they were deemed fit enough to undergo intensive chemotherapy with FCR. As a result, the median age of patients enrolled in the trial was 62 whereas the median age at which CLL is diagnosed is 70. Nevertheless, 31.2% of the patients enrolled were over age 65. The study was funded by Cancer Research UK with additional support from Janssen, Inc., and AbbVie, Inc. This study will publish in the New England Journal of Medicine at 4:30 p.m. on Sunday, Dec. 10, 2023. Peter Hillmen, MB ChB, PhD, of the University of Leeds in the United Kingdom, will present this study during an oral presentation on Sunday, Dec. 10, 2023, at 4:30 p.m. Pacific time in Seaport Ballroom ABCD (Manchester Grand Hyatt San Diego). Presence of measurable residual disease after two chemo cycles predicts benefit from donor transplant in AML with NPM1 mutation 425: The Benefit of Allogeneic Transplant in 1st Complete Remission in NPM1 Mutated AML with or without FLT3 ITD Is Restricted to Those Testing MRD Positive after Induction – an Analysis of the UK NCRI AML17 and AML19 Studies Among patients who have acute myeloid leukemia (AML) with genetic mutations in NPM1, those with no residual leukemia cells in the blood based on high-sensitivity testing after two cycles of chemotherapy achieved high rates of overall survival at three years and saw no additional survival benefit from undergoing a donor stem cell transplant. Conversely, among patients who had residual leukemia cells in the blood, those who received a donor stem cell transplant had improved survival compared with those who did not undergo a transplant. "To our knowledge, this is the largest study to examine whether measurable residual disease (MRD) after two cycles of chemotherapy could identify which patients with NPM1 mutated AML would benefit from a transplant," said Jad Othman, MBBS, of Guy's and St Thomas' NHS Foundation Trust in London and the study's presenting investigator. "In all of the disease subgroups we looked at, the answer is yes, it did – and it was the only thing that did." In the current study, patients who were MRD positive had improved survival when they received a stem cell transplant, whereas among patients who were MRD negative, researchers could not identify any subgroup that showed a survival benefit from a transplant, Dr. Othman explained. AML, a fast-growing cancer of the blood-forming cells in the bone marrow, is classified as favorable risk, intermediate risk, or adverse risk based on the presence or absence of certain genetic mutations, he said. While a transplant of healthy blood cells from a donor can sometimes be a cure for AML, studies have shown that patients with a favorable risk generally do well with chemotherapy and that the risks and side effects of a transplant outweigh the benefits. On the other hand, patients with adverse-risk AML generally do poorly with chemotherapy and are likely to benefit from a transplant. For patients with intermediate-risk AML, Dr. Othman said, the relative benefits of chemotherapy and donor stem cell transplantation are unclear. The NPM1 mutation is the most common genetic risk factor seen in younger adult patients (that is, those aged under 60) with AML. Patients with the NPM1 mutation are generally deemed to be favorable risk, whereas those with the FLT3 mutation are considered intermediate risk. For the subgroup of patients with both mutations, however, it's been unclear whether chemotherapy alone or chemotherapy followed by a transplant is the best approach. Othman and his colleagues analyzed MRD data from 737 patients with NPM1-mutated AML who had achieved a complete response after being treated in one of two large phase three randomized clinical trials, known as AML17 and AML19, that were conducted in the United Kingdom, Denmark, and New Zealand. Both trials enrolled adult patients fit for intensive chemotherapy with newly diagnosed AML. A subset of 238 patients had both NPM1 and FLT3 mutations. The researchers compared patients' outcomes based on their mutation status (NPM1 only or both NPM1 and FLT3), whether or not they underwent a donor transplant, and whether they were MRD positive or MRD negative when tested after two rounds of chemotherapy. Across both trials, among MRD-negative patients, three-year overall survival was 75% for those enrolled in AML17 and 83% for those in AML19. Undergoing a donor transplant did not further improve survival for patients who were MRD negative. By contrast, three-year overall survival among MRD-positive patients who underwent a donor transplant was 61%, compared with 24% for those who did not receive a donor transplant. In the subset of patients with both NPM1 and FLT3 mutations who were MRD-positive, three-year overall survival was 22% in AML17 and 31% in AML19, and patients undergoing transplant had improved survival. Among those with both mutations who were MRD negative, three-year overall survival was 75% in AML17 and 80% in AML19. Again, for those who were MRD negative, undergoing a donor transplant did not improve survival. "Patients who are MRD negative after two courses of chemotherapy have a low risk for relapse," Dr. Othman said. "We saw no evidence that donor transplantation was of benefit to MRD-negative patients, including those with the FLT3 mutation. By contrast, we saw a significant survival benefit for MRD-positive patients who underwent a donor transplant after achieving a complete response to chemotherapy. We think this supports making MRD status after two rounds of chemotherapy a major part of the process for selecting patients who are likely to benefit from transplantation." A limitation of the study findings, he said, is that there are several methods of high-sensitivity testing for MRD, and it's unclear whether the use of a different testing method would have produced the same results. Moreover, not all cancer treatment centers currently have access to high-sensitivity testing. The study was funded by the Cancer Research UK. Jad Othman, MBBS, of Guy's and St Thomas' NHS Foundation Trust in London, will present this study during an oral presentation on Sunday, December 10, 2023, at 10:30 a.m. Pacific time in Marriott Grand Ballroom 8-9 (Marriott Marquis San Diego Marina). For relapsed DLBCL patients who achieve complete remission, two-year outcomes are better with ASCT than with CAR-T 781: Autologous Transplant (auto-HCT) Is Associated with Improved Clinical Outcomes Compared to CAR-T Therapy in Patients (pts) with Large B-Cell Lymphoma (LCBL) Achieving a Complete Remission For patients with a common type of lymphoma who have an early relapse or whose cancer doesn't respond to first-line treatment, randomized trials have shown that CAR T-cell therapy – which involves infusing the patient with their own genetically modified T cells – is superior to the historical standard of care, which included additional chemotherapy followed by high-dose chemotherapy plus a transplant of the patient's own stem cells. Due to the high demand for CAR T-cell therapy, however, patients often face long waits to receive it and need additional chemotherapy as a "bridge" to CAR-T. For some of these patients, that bridging chemotherapy may bring about a complete remission. A new study based on data from the world's largest database of patients treated with stem cell transplants, CAR-T, and similar therapies finds that when patients in complete remission received high-dose chemotherapy plus a transplant of their own stem cells (known as an autologous transplant, or ASCT), they had fewer second relapses and their cancer stayed in remission for longer, compared with similar patients who received CAR T-cell therapy. Two years after treatment, 27.8% of patients treated with ASCT experienced another relapse, compared with 48% of those treated with CAR T-cell therapy. Diffuse large B-cell lymphoma, or DLBCL, is one of the most common types of lymphoma, a cancer that starts in white blood cells. Around 60% of patients with newly diagnosed DLBCL respond well to chemotherapy and don't need further treatment, said Mazyar Shadman, MD, MPH, associate professor at Fred Hutchinson Cancer Center and the University of Washington in Seattle and the study's lead author. For patients whose disease either does not respond to initial chemotherapy or recurs within 12 months, high-dose chemotherapy plus ASCT has historically been the standard of care. Now, however, these patients are eligible to receive CAR T-cell therapy. "Our findings support high-dose chemotherapy plus ASCT as a valid treatment option in real-world practice for patients who achieve a complete remission and also for the subset of patients who have relapsed and may be candidates for CAR T-cell therapy, but achieve a complete remission with bridging chemotherapy," said Dr. Shadman. "ASCT also remains the treatment choice in patients with late relapse who achieve a complete remission as there is not data to suggest that CAR-T is more efficacious." The results are consistent with a previous finding by Dr. Shadman and his colleagues that relapsed patients who achieved partial remission had improved outcomes with ASCT compared with CAR T-cell therapy. Partial remission means tests show a reduction of 50% or more in the number of cancer cells. Complete remission means tests show no signs of cancer. "If they relapse again after ASCT, they still have the option of undergoing CAR T-cell therapy – but it's more difficult to do high-dose chemo plus ASCT if they relapse after CAR T-cell therapy," he said. Dr. Shadman and his colleagues analyzed data from the Center for International Blood & Marrow Transplantation Research (CIBMTR) database to compare outcomes for patients with relapsed DLBCL who were treated with either ASCT or CAR T-cell therapy. The CIBMTR database includes clinical information for more than 630,000 patients worldwide who have been treated with autologous or donor stem cell transplants, CAR T-cell therapies, and other cellular therapies, including most of those treated in the United States. In 2022, Dr. Shadman and his team reported in the journal Blood their findings for 411 adult patients with relapsed DLBCL who received either CAR T-cell therapy or ASCT while in partial remission. They found that patients who received ASCT had fewer relapses and lived longer than those treated with CAR T-cell therapy. For the current study, the researchers compared outcomes for 360 adult patients (average age about 62) with relapsed DLBCL who received either CAR T-cell therapy or ASCT while in complete remission. The study's primary endpoints were the length of time patients stayed in remission (progression-free survival, or PFS) and patients' overall survival (OS). Results showed that patients in the ASCT group had longer remissions and lived longer than those in the CAR T group (PFS, 66.2%; OS, 78.9% for the ASCT group versus PFS, 47.8%; OS, 65.6% for the CAR T group). A limitation of the study is that it is based on a look back at outcomes for patients treated in the past, rather than a clinical trial in which patients were assigned at random to receive ASCT or CAR T-cell therapy, Dr. Shadman said. Mazyar Shadman, MD, MPH of Fred Hutchinson Cancer Center and the University of Washington in Seattle, will present this study during an oral presentation on Monday, Dec. 11, 2023, at 10:30 a.m. Pacific time in the Pacific Ballroom Salons 18-19 (Marriott Marquis San Diego Marina). ### The American Society of Hematology (ASH) (hematology.org) is the world's largest professional society of hematologists dedicated to furthering the understanding, diagnosis, treatment, and prevention of disorders affecting the blood. For more than 60 years, the Society has led the development of hematology as a discipline by promoting research, patient care, education, training, and advocacy in hematology. ASH's flagship journal, Blood (bloodjournal.org) is the most cited peer-reviewed publication in the field, and Blood Advances (bloodadvances.org) is an open-access, online journal that publishes more peer-reviewed hematology research than any other academic journal worldwide. Two new journals will be joining the Blood Journals portfolio in 2024, Blood Neoplasia (bloodneoplasia.org) and Blood Vessels, Thrombosis & Hemostasis (bloodvth.org). SOURCE American Society of Hematology

Aprocitentan is an investigational antihypertensive drug with a novel mechanism of action RARITAN, N.J., Nov. 7, 2022 /PRNewswire/ -- The Janssen Pharmaceutical Companies of Johnson & Johnson, in collaboration with Idorsia Ltd, today announced results from the Phase 3 PRECISION study, which found aprocitentan, an investigational, novel dual endothelin receptor antagonist (ERA), significantly reduced blood pressure (BP) and maintained the effect for up to 48 weeks when added to standardized combination background antihypertensive therapy in patients with difficult-to-control hypertension (sometimes referred to as resistant hypertension). These data were presented as a Late-Breaking Science presentation during the American Heart Association (AHA) Scientific Sessions 2022 (Session: LBS.09) and simultaneously published in The Lancet. Hypertension (HTN), or high BP (usually defined as 140/90 mmHg or above), is one of the leading causes of cardiovascular disease worldwide, impacting an estimated 1.3 billion people globally.i Approximately 10% of these people have difficult-to-control HTN, despite receiving at least three antihypertensive medications.ii,iii Research has suggested difficult-to-control HTN may be due to a lack of treatment targeting all the underlying mechanisms of the condition, in particular the endothelin (ET) pathway, which plays an important role in the development of HTN.iii,iv Compared with adults whose HTN is well controlled, adults with difficult-to-control HTN have greater risk of heart attack, stroke, end-stage renal disease (ESRD) and heart failure.v "The challenge to achieve better BP control in patients with resistant hypertension is at least in part due to the fact that currently available treatment options leave relevant pathophysiologic mechanisms unopposed," said Prof. Markus Schlaich, M.D., FAHA, FESC, ISHF, The University of Western Australia / Royal Perth Hospital, an investigator in the PRECISION study.1 "The results of PRECISION demonstrate aprocitentan is a novel and generally well-tolerated potential treatment strategy for resistant hypertension with clinically meaningful and sustained blood pressure lowering effect." PRECISION evaluated the short-term and sustained effects of aprocitentan on BP lowering when added to standardized combination background antihypertensive therapy in patients with difficult-to-control HTN. A total of 730 hypertensive patients with difficult-to-control HTN were enrolled in the three-part study: From baseline through week 4 (part 1), the double-blind period, patients were randomized to receive aprocitentan 12.5 mg (n=243), aprocitentan 25 mg (n=243), or placebo (n=244) in a 1:1:1 ratio. From weeks 4-36 (part 2), the single-blind period, patients who continued to part 2 (n=704) received 25 mg aprocitentan. From weeks 36-48 (part 3), the double-blind withdrawal period, patients were re-randomized to receive either aprocitentan 25 mg (n=307) or placebo (n=307) in a 1:1 ratio. At baseline, 69.2% of patients were obese or severely obese, 54.1% had diabetes, 22.2% had stage 3-4 chronic kidney disease and 19.6% had congestive heart failure. Key PRECISION Findings The PRECISION study met its primary efficacy endpoint, which was the change in sitting systolic blood pressure (SBP), as measured by unattended automated office BP, from baseline to week 4. Specifically, after 4 weeks, aprocitentan significantly reduced SBP compared with placebo (mean change of -15.3 mmHg for aprocitentan 12.5 mg dose, -15.2 mmHg for 25 mg dose and -11.5 mmHg for placebo, for a difference versus placebo of -3.8 mmHg in the 12.5 mg group [97.5% confidence interval [CI]: -6.8, -0.8; p = 0.0042] and -3.7 mmHg in the 25 mg group [97.5% CI: -6.7, -0.8; p=0.0046]). In addition to meeting its primary endpoint, the study also met its key secondary efficacy endpoint, showing sustained SBP lowering in patients receiving aprocitentan compared to placebo between week 36 and week 40. Specifically, at week 40, SBP increased with placebo compared to aprocitentan 25 mg, for a significant difference of +5.8 mmHg (95% CI: +3.7, +7.9; p<0.0001). This difference was sustained for the final part of the study (the entire 12-week double-blind withdrawal period), up to 48 weeks. Other key findings included: Similar BP lowering effects for aprocitentan were observed with ambulatory BP monitoring, which measured BP in regular intervals over a 24-hour period, at both week 4 and week 40. Specifically, the ambulatory SBP results at week 4 showed greater BP lowering effects with aprocitentan compared with placebo (12.5 mg dose: -4.2 mmHg, 95% CI: -6.2, -2.1; 25 mg dose: -5.9 mmHg, 95% CI: -7.9, -3.8). At week 40, 24-hour ambulatory SBP increased with placebo compared with aprocitentan (+6.5 mmHg; 95% CI: +4.6, +8.5). Treatment effect of aprocitentan was consistent across various prespecified subgroups, including sex, age, body mass index, race and geographic area. Treatment-emergent adverse events (TEAEs) during the 4-week double-blind study period (Part 1) were reported in 28% and 37% of the patients treated with 12.5 and 25 mg aprocitentan, respectively, versus 19% in the placebo group. The most frequent adverse event with aprocitentan was mild-to-moderate fluid retention leading to discontinuation in seven patients during the study. Fluid retention was reported more frequently with aprocitentan than with placebo in a dose-dependent fashion (9.1%, 18.4%, and 2.1% for patients receiving aprocitentan 12.5 mg, 25 mg and placebo, during Part 1, respectively; 18.2% for patients receiving aprocitentan 25 mg during Part 2; and 2.6% and 1.3% for patients on aprocitentan 25 mg and placebo, during Part 3, respectively). "Identifying innovative approaches and novel therapies to help address some of the greatest unmet needs for patients around the world is the cornerstone of our research and development efforts. This is especially true for patients with difficult-to-control hypertension where it is critical that novel pathways are discovered to address a decades old need," said James List, M.D., Ph.D., Global Therapeutic Area Head, Cardiovascular, Metabolism, Retina & Pulmonary Hypertension, Janssen Research & Development, LLC. "The potential addition of aprocitentan to the armamentarium holds promise for these patients." About PRECISION Sponsored by Idorsia, PRECISION was conducted across 193 sites in 22 countries worldwide. All eligible study participants were required to have uncontrolled BP, defined as sitting systolic BP (measured as unattended automated office BP ≥140 mmHg), despite the use of at least three antihypertensive medications from different classes within the previous year. During screening, all patients switched from their respective antihypertensive therapies (except beta-blockers) to standardized background therapy, including a calcium channel blocker (amlodipine), an angiotensin receptor blocker (valsartan), and a diuretic (hydrochlorothiazide), which they received for at least four weeks before entering the second part. Patients then received placebo in addition to standardized background therapy for four additional weeks. This was followed by the active treatment period of the study, which included the three sequential parts. The safety follow-up period covered the 30 days after the last study treatment dose. The effect on systolic and diastolic blood pressure was measured at trough by unattended automated office blood pressure (AOBP), and by 24-hour ambulatory blood pressure monitoring (ABPM) throughout the 48-week treatment period. More information can be found on (NCT03541174). About aprocitentan Aprocitentan is an investigational, novel, oral, dual ERA, which potently inhibits the binding of ET-1 to ETA and ETB receptors. Aprocitentan has a low potential for drug-drug interaction and a mechanism of action that is intended to address the pathophysiology of difficult-to-control HTN. About the Janssen/Idorsia Collaboration In 2017, Janssen Biotech, Inc., one of the Janssen Pharmaceutical Companies of Johnson & Johnson, entered into a collaboration agreement with Idorsia to jointly develop aprocitentan and any of its derivative compounds or products. Both parties have joint development rights over aprocitentan. Idorsia has conducted the Phase 3 development and will be responsible for the regulatory submission for the indication of the treatment of patients with difficult-to-control HTN. About the Janssen Pharmaceutical Companies of Johnson & Johnson At Janssen, we're creating a future where disease is a thing of the past. We're the Pharmaceutical Companies of Johnson & Johnson, working tirelessly to make that future a reality for patients everywhere by fighting sickness with science, improving access with ingenuity, and healing hopelessness with heart. We focus on areas of medicine where we can make the biggest difference: Cardiovascular, Metabolism, & Retina; Immunology; Infectious Diseases & Vaccines; Neuroscience; Oncology; and Pulmonary Hypertension. Learn more at . Follow us at @JanssenGlobal and @JanssenUS. Janssen Research & Development, LLC and Janssen Biotech, Inc. are part of the Janssen Pharmaceutical Companies of Johnson & Johnson. Cautions Concerning Forward-Looking Statements This press release contains "forward-looking statements" as defined in the Private Securities Litigation Reform Act of 1995 regarding product development and the potential benefits and treatment impact of aprocitentan. The reader is cautioned not to rely on these forward-looking statements. These statements are based on current expectations of future events. If underlying assumptions prove inaccurate or known or unknown risks or uncertainties materialize, actual results could vary materially from the expectations and projections of Janssen Research & Development, LLC, or any of the other Janssen Pharmaceutical Companies and/or Johnson & Johnson. Risks and uncertainties include, but are not limited to: challenges and uncertainties inherent in product research and development, including the uncertainty of clinical success and of obtaining regulatory approvals; uncertainty of commercial success; manufacturing difficulties and delays; competition, including technological advances, new products and patents attained by competitors; challenges to patents; product efficacy or safety concerns resulting in product recalls or regulatory action; changes in behavior and spending patterns of purchasers of health care products and services; changes to applicable laws and regulations, including global health care reforms; and trends toward health care cost containment. A further list and descriptions of these risks, uncertainties and other factors can be found in Johnson & Johnson's Annual Report on Form 10-K for the fiscal year ended January 2, 2022, including in the sections captioned "Cautionary Note Regarding Forward-Looking Statements" and "Item 1A. Risk Factors," and in Johnson & Johnson's subsequent Quarterly Reports on Form 10-Q, and other filings with the Securities and Exchange Commission. Copies of these filings are available online at , or on request from Johnson & Johnson. None of the Janssen Pharmaceutical Companies nor Johnson & Johnson undertakes to update any forward-looking statement as a result of new information or future events or developments. 1 Professor Schlaich received payment for his participation in the PRECISION study. i NCD Risk Factor Collaboration (NCD-RisC). Worldwide trends in hypertension prevalence and progress in treatment and control from 1990 to 2019: a pooled analysis of 1201 population-representative studies with 104 million participants. Lancet 2021;398:957-80. ii Noubiap JJ, Nansseu JR, Nyaga UF, Sime PS, Francis I, Bigna JJ. Global prevalence of resistant hypertension: a meta-analysis of data from 3·2 million patients. Heart 2019; 105: 98–105 / iii Williams B, Mancia G, Spiering W, et al. 2018 ESC/ESH guidelines for the management of arterial hypertension. Eur Heart J 2018; 39: 3021–104. ivClozel M. Aprocitentan and the endothelin system in resistant hypertension. Can J Physiol Pharmacol 2022;100:573-83. vDaugherty SL, Powers JD, Magid DJ, Tavel HM, Masoudi FA, Margolis KL, O'Connor PJ, Selby JV, Ho PM. Incidence and prognosis of resistant hypertension in hypertensive patients. Circulation. 2012 Apr 3;125(13):1635-42. Me d i a Contact: Jennifer Silvent Phone: +1 973-479-9845 [email protected] Tina Kitt Phone: +41 79-219-8643 [email protected] Investor C on t ac t : Raychel Kruper Phone: +1 732-524-6164 [email protected] SOURCE Janssen Pharmaceutical Companies of Johnson & Johnson

Unveiled a new preclinical program focused on developing iPSC derived gamma-delta T cells and presented early findings at the ASGCT Annual Meeting.Presented data from Phase 1 clinical trial of INB-200 in patients with newly diagnosed GBM showing five of six fully dosed patients exceeded both median and expected progression free survival (PFS), with a sixth patient early in follow up; two patients have exceeded overall survival (OS) benchmarks established by Stupp et al, 2005 to-date.Continued to demonstrate durable morphologic complete responses from INB-100 Phase 1 clinical trial in leukemia patients with two of three patients relapse free at two years to date and all three relapse free past one year.Appointed seasoned executives to the roles of Senior Vice President, Business Development, Vice President, Regulatory Affairs, and Vice President, Clinical Operations. NEW YORK, Aug. 12, 2022 (GLOBE NEWSWIRE) -- IN8bio, Inc. (Nasdaq: INAB), a clinical-stage biopharmaceutical company focused on discovering and developing innovative gamma-delta T cell therapies that utilize its DeltEx platform, today announced financial results and operational highlights for the quarter ended June 30, 2022. In addition, the Company provided an overview of recent corporate developments. “Our team continues to execute and advance our gamma-delta programs on multiple fronts. Our Phase 1 clinical trials for both DeltEx product candidates, INB-200 in GBM and INB-100 in leukemia patients undergoing stem cell transplantation, continue to progress with encouraging durability data. We introduced our iPSC derived gamma-delta T cell platform at the ASGCT annual meeting, and we have been receiving positive feedback on this new program,” said William Ho, CEO and co-founder of IN8bio. “During the quarter and into July, we continued to expand our management team; we have attracted talented individuals who have built their careers and established their reputations in well-recognized companies like Genentech, Novartis, Janssen, Bristol Myers Squibb and Covance. We believe they will be instrumental in shaping IN8bio’s future. The IN8bio team continues to be disciplined, and we are working to dedicate our resources to accelerating IN8bio’s growth and momentum.” Business Highlights & Clinical Updates In May 2022, IN8bio unveiled a new preclinical program focused on developing induced pluripotent stem cell (iPSC) derived gamma-delta T cells and presented its early findings at the American Society of Gene and Cell Therapy (ASGCT) Annual Meeting. Uniquely, IN8bio has been able to demonstrate the ability to derive both Vd1+ and Vd2+ iPSC gamma-delta T cell clones. These iPSC-derived gamma-delta T cells demonstrated robust cytotoxicity and can be genetically modified with an internally developed chimeric antigen receptor (CAR-T) construct at a high transduction yield. Scalable iPSC-based cellular manufacturing is designed to create for a uniform and renewable therapeutic product available “off-the-shelf” for patients.In June 2022, IN8bio provided an update on the INB-200 Phase 1 clinical trial in newly diagnosed glioblastoma multiforme (GBM) patients at the 2022 American Society of Clinical Oncology (ASCO) Annual Meeting. Five of six fully dosed patients exceeded both median and expected progression-free survival (PFS), and two patients exceeded the expected overall survival (OS) benchmarks as of June 3, 2022. All patients demonstrated a manageable toxicity profile with no evidence of cytokine release syndrome (CRS), tumor lysis syndrome (TLS) or immune effector cell-associated neurotoxicity syndrome (ICANS).In June 2022, IN8bio held a successful pre-investigational new drug application (pre-IND) meeting with the Food and Drug Administration. The meeting provided guidance and confirmed IND filing requirements for the INB-400 program. IN8bio expects to file the IND by year-end.In July 2022, IN8bio announced a patent covering the composition of matter for IN8bio’s Drug Resistant Immunotherapy (DRI) platform. The patent broadens the Company’s intellectual property coverage of genetically engineered innate immune cells beyond gamma-delta T cells to include NK cells.In July 2022, IN8bio provided an update from the ongoing Phase 1 clinical trial of INB-100 in leukemia patients undergoing haploidentical stem cell transplantation. All three high-risk AML patients from the first cohort continue to demonstrate durable morphologic complete responses (CR) and remain progression-free and alive for more than one year. Two of the three patients remain in morphologic CR for more than two years. The safety profile continues to be manageable with no dose-limiting toxicities. Recent Team Growth In April 2022, IN8bio announced the expansion of its clinical and regulatory teams with the appointments of Urvashi Patel, Ph.D., Vice President, Regulatory Affairs, and Stacey Bilinski, Vice President, Clinical Operations. They bring more than a combined 45 years of clinical and regulatory experience to the IN8bio team. In July 2022, IN8bio appointed Kenneth R. LaMontagne, Ph.D., as Senior Vice President, Business Development to lead the Company’s business development activities. Dr. LaMontagne is an industry leader with more than 20 years of experience, including licensing, collaborations, search and evaluation, M&A and corporate strategy including in the fields of cell therapy and oncology. He gained his experience in both large pharma and small biopharmaceutical companies. Second Quarter 2022 Financial ResultsResearch and development (R&D) expenses were $3.5 million for the three months ended June 30, 2022, compared to $2.1 million for the comparable prior year period. The increase in R&D expenses were primarily due to (i) increased third-party clinical trial and IND-related activities, (ii) contract manufacturing costs for the ongoing INB-200 clinical trial and (iii) increased personnel-related costs, including salaries, benefits and stock-based compensation due to increased headcount. General and administrative expenses were $3.7 million for the three months ended June 30, 2022, compared to $1.0 million for the comparable prior year period. The increase was primarily due to increased headcount, insurance, legal expenses, and expenses associated with operating as a public company. The Company reported a net loss attributable to common stockholders of $7.2 million, or $0.38 per basic and diluted common share, for the three months ended June 30, 2022, compared to a net loss attributable to common stockholders of $3.8 million, or $1.00 per basic and diluted common share, for the comparable prior year period. As of June 30, 2022, the Company had cash of $25.7 million, compared to $37.0 million as of December 31, 2021. The decrease in cash was primarily due to cash used by the Company in R&D and continued operations to advance its programs along with ongoing construction of a state-of-the-art ~10,000 sq. ft. R&D facility in Birmingham, AL. About IN8bioIN8bio is a clinical-stage biopharmaceutical company focused on the discovery, development and commercialization of gamma-delta T cell product candidates for solid and liquid tumors. Gamma-delta T cells are a specialized population of T cells that possess unique properties, including the ability to differentiate between healthy and diseased tissue. IN8bio’s DeltEx platform employs allogeneic, autologous, iPSC and genetically modified approaches to develop cell therapies, designed to effectively identify and eradicate tumor cells. IN8bio is currently conducting two investigator-initiated Phase 1 clinical trials for its lead gamma-delta T cell product candidates: INB-200 for the treatment of newly diagnosed glioblastoma and INB-100 for the treatment of patients with leukemia undergoing hematopoietic stem cell transplantation. IN8bio also has a broad portfolio of preclinical programs focused on addressing other solid tumor types. For more information about IN8bio and its programs, please visit www.IN8bio.com. Forward Looking StatementsThis press release may contain forward-looking statements made pursuant to the safe harbor provisions of the Private Securities Litigation Reform Act of 1995. These statements may be identified by words such as “aims,” “anticipates,” “believes,” “could,” “estimates,” “expects,” “forecasts,” “goal,” “intends,” “may,” “plans,” “possible,” “potential,” “seeks,” “will” and variations of these words or similar expressions that are intended to identify forward-looking statements, although not all forward-looking statements contain these words. Forward-looking statements in this press release include, but are not limited to, statements regarding the timing of initiation, progress and scope of clinical trials for IN8bio’s product candidates; the potential of IN8bio’s DeltEx platform to discover and develop innovative product candidates, including iPSC-derived cell therapies; IN8bio’s ability to achieve planned milestones, including data readouts from its trials and plans to file an IND application; and the impact recent management team additions will have on the progression of the Company. IN8bio may not actually achieve the plans, intentions or expectations disclosed in these forward-looking statements, and you should not place undue reliance on these forward-looking statements. Actual results or events could differ materially from the plans, intentions and expectations disclosed in these forward-looking statements as a result of various factors, including: risks to site initiation, clinical trial commencement, patient enrollment and follow-up, as well as IN8bio’s ability to meet anticipated deadlines and milestones, presented by the ongoing COVID-19 pandemic; uncertainties inherent in the initiation and completion of preclinical studies and clinical trials and clinical development of IN8bio’s product candidates; the risk that IN8bio may not realize the intended benefits of its DeltEx platform; availability and timing of results from preclinical studies and clinical trials; whether the outcomes of preclinical studies will be predictive of clinical trial results; whether initial or interim results from a clinical trial will be predictive of the final results of the trial or the results of future trials; the risk that trials and studies may be delayed and may not have satisfactory outcomes; potential adverse effects arising from the testing or use of IN8bio’s product candidates; expectations for regulatory approvals to conduct trials or to market products; IN8bio’s reliance on third parties, including licensors and clinical research organizations; and other important factors, any of which could cause our actual results to differ from those contained in the forward-looking statements, are described in greater detail in the section entitled “Risk Factors” in our Quarterly Report on Form 10-Q filed with the Securities and Exchange Commission (SEC) on May 12, 2022, as well as in other filings IN8bio may make with the SEC in the future. Any forward-looking statements contained in this press release speak only as of the date hereof, and IN8bio expressly disclaims any obligation to update any forward-looking statements contained herein, whether because of any new information, future events, changed circumstances or otherwise, except as otherwise required by law. IN8BIO, INC.CONDENSED BALANCE SHEETS(In thousands, except share and per share data) June 30, 2022 December 31, (unaudited) 2021 Assets Current assets Cash $25,742 $37,021 Prepaid expenses and other current assets 1,257 1,959 Total Current Assets 26,999 38,980 Non-current assets Property and equipment, net 220 97 Construction in progress 1,405 403 Restricted cash 252 251 Right of use assets - financing leases 453 704 Right of use assets - operating leases 1,413 1,630 Other non-current assets 246 158 Total Non-Current Assets 3,989 3,243 Total Assets $30,988 $42,223 Liabilities and Stockholders' Equity Liabilities Current liabilities Accounts payable $887 $395 Accrued expenses and other current liabilities 1,525 1,235 Short-term financing lease liability 299 392 Short-term operating lease liability 261 234 Total Current Liabilities 2,972 2,256 Long-term financing lease liability 132 269 Long-term operating lease liability 1,316 1,515 Total Non-Current Liabilities 1,448 1,784 Total Liabilities 4,420 4,040 Commitments and Contingencies Stockholders' Equity Common stock, par value $0.0001 per share; 490,000,000 shares authorized at June 30, 2022 and December 31, 2021; 18,838,471 and 18,781,242 shares issued and outstanding at June 30, 2022 and December 31, 2021, respectively 2 2 Additional paid-in capital 72,581 70,872 Accumulated deficit (46,015) (32,691)Total Stockholders' Equity 26,568 38,183 Total Liabilities and Stockholders' Equity $30,988 $42,223 IN8BIO, INC. CONDENSED STATEMENTS OF OPERATIONS (In thousands, except share and per share data) (Unaudited) Three Months EndedJune 30, Six Months EndedJune 30, 2022 2021 2022 2021 Operating expenses: Research and development$3,504 $2,064 $5,885 $3,310 General and administrative 3,675 986 7,439 2,103 Total operating expenses 7,179 3,050 13,324 5,413 Loss from operations (7,179) (3,050) (13,324) (5,413)Net loss$(7,179) $(3,050) $(13,324) $(5,413)Net loss attributable to common stockholders$(7,179) $(3,765) $(13,324) $(6,834)Net loss per share attributable to common stockholders – basic and diluted$(0.38) $(1.00) $(0.71) $(1.82)Weighted-average number of shares used in computing net loss per common share, basic and diluted 18,828,680 3,764,488 18,814,691 3,764,488 Company Contact:IN8bio, Inc.Patrick McCall+ 1 646.600.6GDT (6438)info@IN8bio.com Investors:Solebury TroutDavid Buck+ 1 646.378.2927dbuck@soleburytrout.com Media:Burns McClellan, Inc.Katie Larch / Robert Flamm, Ph.D.+1 212.213.0006klarch@burnsmc.com / rflamm@burmsmc.com